Throughout nature, a decrease in growth, and hence body size within species is associated with increased lifespan. Moreover, lifespan extension resulting from mutations of single genes in the insulin/IGF signaling pathway has pioneered and revolutionized modern studies on the biology of aging. Because epidemiologic studies suggest that low peripheral IGF-1 is associated with a lower risk of cancer but increase risk of CVD, stroke, T2DM, and osteoporosis, we question if all the evidence from other models are relevant to humans. In addition to the known benefits of peripheral and central IGF-1, we have recently uncovered novel positive effects of central IGF-1 action on the periphery, and here we suggest that strategies designed to tip the balance of IGF-1 action from peripheral to central may maximize the 'good' effects of IGF-1 while minimizing the 'bad' effects of IGF-1 on cancer risk. Indeed, our lab has recently uncovered remarkable positive effects of central IGF-1 action including improved peripheral insulin action and selective depletion of visceral fat, suggesting that some actions of IGF-1 may be favorable for aging. This is in contrast to the purported 'bad' effects of peripheral IGF-1 which is linked to increased cancer risk. The overall hypothesis of the research plan is that healthy aging and longevity is best achieved by increasing IGF-1 action in the hypothalamus to reap the 'good' effects while decreasing it in the periphery to avoid the 'bad' effects, such as cancers. Ultimately, these studies may yield important new insights regarding the complex role of IGF-1 on health and aging with relevance to humans. In order to test the overall hypothesis; Aim 1 will focus on the contribution of the hypothalamus in mediating an acute central or peripheral IGF-1 infusion on insulin action by hyperinsulinemic-euglycemic clamp in young and old rats and assess hypothalamic signaling pathways stimulated by IGF-1. Aim 2 focuses on the contribution of the hypothalamus in mediating chronic central or peripheral IGF-1 treatment on body fat distribution and insulin action. The goal of Aim 3 will be to study the lifelong effects of chronic central IGF-1 overexpression by lentivirus targeted to the hypothalamus and lifelong peripheral IGF-1 receptor blockade with an antibody, alone or in combination, on healthy aging and longevity in rats. PUBLIC HEALTH RELEVANCE: Growth hormone/IGF-1 axis is central in aging and longevity, and controversial and it's translation to treatment. Here we suggest that strategies designed to tip the balance of IGF-1 action from peripheral to brain may maximize the good effects of IGF-1 while minimizing the bad effects of IGF-1 on cancer risk, leading to healthy life-span.